FDA Approval Summary: Belzutifan for VHL Disease Tumors—Letter
Authors: Jonathan Q. Trinh, Moataz Ellithi, Nicole Shonka, Raymond C. Bergan
Journal: Clinical Cancer Research (2023)

We read with great interest the article by Fallah and colleagues regarding the FDA approval of belzutifan as the first systemic treatment for von Hippel-Lindau disease (VHL; ref. 1). Despite the demonstrated antitumor activity and overall good safety profile in the clinical trial (2), we believe much is still unknown about belzutifan's potential adverse effects given its novelty. Here, we present the first case of hemorrhage from hemangioblastomas resulting in spinal cord compression coincident with initiation of belzutifan treatment.A 54-year-old male with a history of VHL presented to our clinic seeking belzutifan treatment. He had previously undergone left-sided nephrectomy and right-sided partial nephrectomy for multifocal renal cell carcinoma (RCC), had vision loss due to retinal hemangioblastomas, and was undergoing active surveillance for suprasellar and cerebellar hemangioblastomas for which he was otherwise asymptomatic. CT imaging at that time demonstrated multiple 2–2.5 cm lesions in his kidney, slightly increased from prior imaging and radiographically consistent with RCC. Four days after starting belzutifan 120 mg, he presented to the emergency department with acute-onset mid-thoracic back pain, bilateral lower extremity loss of sensation and decreased muscle strength, and urinary retention. MRI revealed contrast-enhancing intramedullary lesions at T1 and T2 and hemorrhage with adjacent spinal cord compression. Belzutifan was held and dexamethasone was administered. A C7-T3 laminectomy with partial T1 lesion resection was performed with resultant pathologic examination demonstrating hemorrhagic blood products and no evidence of malignancy, consistent with bleeding from a hemangioblastoma. Over the next 2 months, he experienced continued neurologic recovery.Belzutifan is the first systemic therapy approved for treatment of VHL-associated RCC, central nervous sysytem hemangioblastomas, and pancreatic neuroendocrine tumors. As Fallah and colleagues note, common side effects include anemia and fatigue (1). The case described here closely associates initiation of belzutifan with the occurrence of hemangioblastoma-associated hemorrhage and damage to the neuroaxis. No such adverse effect was reported in the belzutifan clinical trial (2). Though highly vascular tumors, hemangioblastomas have very low rates of spontaneous hemorrhage, less than 0.01% per person per year (3). The rare nature of VHL serves as a barrier to rigorously determining the causal relationship between belzutifan and damage to the neuroaxis. Given these facts, the low rate of spontaneous hemorrhage, and the close temporal links described in the current case report, we recommend imaging of the complete neuroaxis prior to initiation of belzutifan therapy. In addition, postmarketing studies must be performed to thoroughly evaluate its safety profile.See the Response, p. 685R.C. Bergan reports a patent for 8,481,760, 8,742,141, 9,839,625, 10,231,949 issued to no, a patent for 62/628,243 pending to no, and a patent for 62/801,858 pending to license to a third party imminent. No disclosures were reported by the other authors.